Pharmacogenetics Approach for Personalized Tacrolimus Dosing in Heart Transplantation: A Case Report and Literature Review

Background: Tacrolimus is a cornerstone of immunosuppressive therapy following heart transplantation. Despite routine therapeutic drug monitoring (TDM), substantial interindividual variability in tacrolimus pharmacokinetics presents a persistent challenge. Pharmacogenetic profiling—particularly of CYP3A5 and CYP3A4 polymorphisms—offers a promising approach to individualize tacrolimus dosing and improve clinical outcomes. Case Presentation: We describe a 54-year-old male heart transplant recipient with persistently subtherapeutic tacrolimus trough concentrations despite escalating standard doses. Tacrolimus dosing initially started at 3.5 mg twice daily, escalated to 7.0 mg twice daily, with final maintenance dosing at 6.5 mg twice daily. TDM values were persistently subtherapeutic at 3–5 ng/mL for over a month before achieving therapeutic targets >10 ng/mL. Pharmacogenetic testing revealed a CYP3A5 expresser genotype (*1/*3) and normal CYP3A4 activity (*1/*1), suggesting enhanced metabolic clearance. In accordance with CPIC guidelines, tacrolimus dosing was intensified and supported by co-administration of diltiazem (60 mg twice daily, later adjusted to 90 mg twice daily), a CYP3A4 inhibitor. Subsequent TDM confirmed achievement of therapeutic levels. At nine months post-transplant, the patient exhibited stable graft function and excellent clinical status. Discussion: This case underscores the value of genotype-informed tacrolimus dosing in clinical scenarios where standard TDM is insufficient. Pharmacogenetic variation—particularly involving CYP3A5 expression—has been consistently associated with altered tacrolimus exposure and dose requirements. The literature supports routine genotyping in solid organ transplant recipients, although implementation remains limited. Additional considerations include drug–drug interactions, notably with CYP3A-modulating agents such as diltiazem and antifungals, which may further influence tacrolimus pharmacokinetics. Current evidence suggests that the utility of CYP3A4 genotyping may be phase-dependent, being more impactful during early post-transplant periods. Conclusions: Incorporating pharmacogenetic data alongside TDM facilitates more precise and individualized tacrolimus therapy, optimizing immunosuppressive efficacy and minimizing risk. This case, supported by literature review, advocates for broader integration of genotype-guided strategies in transplant pharmacotherapy.